Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Abdulraheem Almalki (Author) Other; Charlotte L Alston (Author) Other; Alasdair Parker (Author) Other; Ingrid Simonic (Author) Other; Sarju G Mehta (Author) Other; Langping P He (Author) Other; Mojgan Reza (Author) Other; Jorge M A Oliveira (Author) FFUP; Robert N Lightowlers (Author) Other; Robert McFarland (Author) Other; Robert W Taylor (Author) Other; Zofia M A Chrzanowska Lightowlers (Author) Other

Journal

Title: Biochimica et Biophysica Acta - Molecular Basis of Disease

Vol. 1842

Pages: 56-64

ISSN: 0925-4439

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 39 Citations

Scopus - 44 Citations

Scientific classification

FOS: Natural sciences > Biological sciences

Other information

Authenticus ID: P-008-GVK

DOI: 10.1016/j.bbadis.2013.10.008

Abstract (EN): Mitochondrial aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein synthesis since they charge tRNAs with their cognate amino acids. Mutations in the genes encoding mitochondrial aaRSs have been associated with a wide spectrum of human mitochondrial diseases. Here we report the identification of pathogenic mutations (a partial genomic deletion and a highly conserved p. Asp325Tyr missense variant) in FARS2, the gene encoding mitochondrial phenylalanyl-tRNA synthetase, in a patient with early-onset epilepsy and isolated complex IV deficiency in muscle. The biochemical defect was expressed in myoblasts but not in fibroblasts and associated with decreased steady state levels of COXI and COXII protein and reduced steady state levels of the mt-tRNAPhe transcript. Functional analysis of the recombinant mutant p.Asp325Tyr FARS2 protein showed an inability to bind ATP and consequently undetectable aminoacylation activity using either bacterial tRNA or human mt-tRNAPhe as substrates. Lentiviral transduction of cells with wildtype FARS2 restored complex IV protein levels, confirming that the pAsp325Tyr mutation is pathogenic, causing respiratory chain deficiency and neurological deficits on account of defective aminoacylation of mt-tRNAPhe.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 9